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1 HEPATIC CLEARANCE Q x C A Q x C V Q(C A - C V ) Rate of Extraction 1. Mass Balance.

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Presentation on theme: "1 HEPATIC CLEARANCE Q x C A Q x C V Q(C A - C V ) Rate of Extraction 1. Mass Balance."— Presentation transcript:

1 1 HEPATIC CLEARANCE Q x C A Q x C V Q(C A - C V ) Rate of Extraction 1. Mass Balance

2 2 HEPATIC CLEARANCE Extraction Ratio 2. Mass Balance Normalized to Rate of Entry 1 1 - E E

3 3 HEPATIC CLEARANCE Clearance 3. Mass Balance Normalized to C A Q Q(1 – E) Q x E

4 4 Recall that CL = QE; hence CL H = Q H E CL H = hepatic clearance Q H = hepatic blood flow E = hepatic extraction ratio Q H - from 1.0 to 1.5 L/min E – ranges from 0 to 1

5 5 Recall that CL = QE; hence CL H = Q H E Thus, if the non-renal clearance of a drug exceeds Q H, some form of non-renal and non- hepatic elimination must take place.

6 6 Example: (labetalol) CL T = 2.344 L/min CL R = 0.08 L/min V ss = 685 L t 1/2 = 6 hr Can the nonrenal clearance be attributed solely to hepatic elimination?

7 7 CL H = Q H E Suggests that CL H ~ Q H Actually Q H = E

8 8 VENOUS EQUILIBRIUM MODEL QC i n QC out Elimination

9 9 SINUSOIDAL MODEL QC i n QC out Elimination

10 10 Intrinsic hepatic clearance: The ability of the liver to remove xenobiotic from the blood in the absence of other confounding factors (e.q., Q H ).

11 11 Since CL H = Q H E

12 12

13 13 Quantitative Assessment of Hepatic Clearance Assuming the Venous Equilibrium Model

14 14

15 15

16 16 Limits:

17 17 Limits:

18 18

19 19 Limits:

20 20 Limits:

21 21 Compounds with a high CL int, are said to exhibit perfusion rate- limited elimination.

22 22 From: Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications, 3 rd edition, 1995, p. 162

23 23 HEPATIC EXTRACTION RATIO OF REPRESENTATIVE DRUGS Low (<0.3) Antipyrine Diazepam Phenylbutazone Theophylline Tolbutamide Warfarin High (>0.7) Lidocaine Meperidine Propoxyphene Propranolol Verapamil Intermediate: Quinidine

24 24 Consider the case of administering a constant infusion of a drug with the following conditions: CL int = 7.0 L/min, Q H = 1.0 L/min K o = 1.0 mg/min Assuming drug is eliminated completely via hepatic metabolism, what would the steady-state concentration be?

25 25

26 26 What if the pt developed CHF resulting in a 25% reduction in Q H ?

27 27 In contrast, suppose we administer a low CL int ? CL int = 0.01 L/min, Q H = 1.0 L/min K 0 = 0.1 mg/min

28 28 What if Q H were reduced by 25%

29 29 FIRST-PASS EFFECT HEART GUT LIVER BODY

30 30 HEART GUT LIVER BODY

31 31 HEART GUT LIVER BODY

32 32 HEART GUT LIVER BODY

33 33 HEART GUT LIVER BODY

34 34 HEART GUT LIVER BODY

35 35 If a drug is completely absorbed after oral administration, the fraction of the oral dose that reaches the systemic circulation (F) is given as F = 1 - E Remembering that

36 36 Q H >> CL int, F 1 Q H << CL int, F 0

37 37

38 38 Determination of CL int after oral dosing: Assumes: Drug is completely absorbed No extrahepatic metabolism System is stationary

39 39 Determination of CL int after oral dosing:

40 40 Determination of CL int after oral dosing:

41 41 Estimated in this fashion the CL int is often referred to as the oral clearance (CL o ) For a high CL int drug:

42 42 Estimated in this fashion the CL int is often referred to as the oral clearance (CL o ) For a low CL int drug:

43 43 Consider a high clearance drug (e.g., propranolol) after oral and IV dosing: CL int = 10 L/min, Q H = 1.5 L/min

44 44 What would happen to CL H is Q H were reduced to 1.0 L/min? What if drug were administered orally under these conditions?

45 45

46 46 How would a decrease in Q H affect this?

47 47 But what happens to AUC? For control conditions: When Q H is decreased:

48 48 IMPACT OF PROTEIN BINDING CL int = f ub CL uint

49 49

50 50 Effect of protein binding on warfarin clearance in the rat. Data from Yacobi A, Levy G. J Pharm Sci 64:1660, 1975.

51 51 Effect of protein binding on warfarin clearance in humans. Data from Routledge et al. Br J Clin Pharmacol 8:243, 1979.

52 52 CL uint = 0.25 L/min Q H = 1.5 L/min f ub = 0.1 K 0 = 0.25 mg/min

53 53 CL uint = 0.25 L/min Q H = 1.5 L/min f ub = 0.1 K 0 = 0.25 mg/min

54 54 What if f ub = 0.2?

55 55 What if f ub = 0.2?

56 56 What happens to free concentration?

57 57 What about oral administration?

58 58 Consider a high clearance drug iv: CL uint = 30 L/min Q H = 1.5 L/min f ub = 0.25 K 0 = 2 mg/min

59 59 Consider a high clearance drug iv: CL uint = 30 L/min Q H = 1.5 L/min f ub = 0.25 K 0 = 2 mg/min

60 60 What if f ub = 0.5?

61 61 What if f ub = 0.5?

62 62 What about oral administration?

63 63 What if f ub = 0.5?

64 64 What if f ub = 0.5?

65 65 Effect of displacement (D) of plasma protein binding on total and unbound concentrations of drug From: Rowland M, Tozer TN. Clinical Pharmacokinetics – Concepts and Applications, 3 rd edition

66 66 From: Rowland M, Tozer TN. Clinical Pharmacokinetics – Concepts and Applications, 3 rd edition

67 67 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration E 0.1 CL int 0.167 L/min CL H 0.150 L/min Time 0.18 0.334 L/min 0.273 L/min

68 68 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration Time

69 69 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration E 0.90 CL int 13.7 L/min CL H 1.35 L/min Time 0.95 27.0 L/min 1.42 L/min

70 70 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 0.1 0.01 Blood Concentration Time

71 71 Effect of rifampin on the kinetics of warfarin after a single dose before (open circles) and after (closed circles) treatment with rifampin 600 mg/day. From: OReilly RA. Interaction of sodium warfarin and rifampin. Ann Intern Med 81:337-40, 1974.

72 72

73 73 Effect of pentobarbital on alprenolol disposition. Alprenolol was administered before (O, closed, iv, open oral) and after 10 d of pentobarbital ( ). Reproduced from Alvan G, et al. Clin Pharmacol Ther 22:316-321, 1977.

74 74 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration E 0.1 Q H 1.50 L/min CL H 0.150 L/min Time 0.18 0.75 L/min 0.135 L/min

75 75 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration Time

76 76 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration E 0.90 Q H 1.50 L/min CL H 1.35 L/min Time 0.95 0.75 L/min 0.71 L/min

77 77 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 0.1 0.01 Blood Concentration Time

78 78 Propoxyphenes CNS depression is enhanced when co- administered with ethanol. To assess the contribution of a pharmacokinetic interaction to this enhancement, propoxyphene was administered iv and po, with and without ethanol. The curves below illustrate the results. What is the mechanism of interaction? TIME Log [Propoxyphene] TIME Log [Propoxyphene] Propoxyphene alonePropoxyphene + ETOH

79 79 Complete the following graphs for a drug with a CL H = 20 mL/min/kg and one with a CL H = 1 mL/min/kg f up CL H f up AUC o

80 80 Complete the following graphs for a drug with a CL H = 20 mL/min/kg and one with a CL H = 1 mL/min/kg f up CL uint QHQH CL H

81 81 Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kg f up CL uint

82 82 Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kg QHQH CL H

83 83 EQ H f ub f ut CL T V ss t 1/2 AUC o High

84 84 EQ H f ub f ut CL T V ss t 1/2 AUC o Low


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